To promote faster healing of infected wounds and burns, reduction of bio-burden is the first step. In quantitative terms, the bio-burden of infected wounds can reach as high as a million colony forming units (cfu) per gram of tissue. Therefore, rapid disinfection of the wounds followed by maintenance of low bio-burden is particularly attractive.
The most widely accepted clinical practice for reducing the bio-burden of the wounds is to cover them with dressings infused with antimicrobial compounds. The choice of wound dressing is dependent on the state of the wound; for badly infected wounds the dressings that release antimicrobial actives to the wounds very rapidly are preferred to cause bacterial count to drop to negligible levels. Thereafter, with optimal moisture management the body's immune system takes over to accelerate healing. A commercial product, Acticoat® is one such dressing that rapidly releases a lethal bolus of ionic silver. While such burst of ionic silver kills bacteria, it also stains skin and in the short term often retards wound healing.
Alternately, there are products that deliver the antimicrobial actives to the wound site more slowly over time. In such case, the bio-burden decrease takes place slowly but without interference with the body's natural healing process. Additionally, these products are compounded with agents that aid healing and provide for moisture management. Examples of such products include antimicrobial hydrogels (SilvaSorb®, SilverSept®, Normlgel Ag® and Elta®) and antimicrobial sheet dressings (SilvaSorb® and Covalon®)
However, in these products, especially the hydrogels, the amount of active silver compound is kept low so that in topical use they are not toxic to the skin cells. In hydrogels, due to their complex compositions and high viscosities, lower amounts of the silver compound often leads to uneven performance because the active species (Ag+ ions) is sometimes prematurely reduced to elemental silver (Ag0) which is inactive against microorganisms. The premature reduction often occurs in the hydrogel compositions in packaged form during storage due to various factors such as interaction with packaging material and changes in environment conditions. Thus, the silver containing compositions currently on the market perform differently when made fresh and may fail as they approach the end of their shelf life. To compensate for decreased activity of the hydrogel product nearing its end of useful life, the formulators often increase the amount of active ionic silver. However, increased amounts of ionic silver in the hydrogels increases the risk of premature reduction due to various factors mentioned earlier. The reduction of the active silver compound to inactive elemental silver in hydrogel compositions is accompanied by undesirable discoloration. In some situations, the hydrogels undergo a change in gel pH to acidic resulting in increased stinging and irritation to the patient's skin. This particularly is extremely undesirable to persons with sensitive skin or those with burns.
While some silver containing antimicrobial products such as Acticoat® dressings are dark colored and have been acceptable, consumer preferences do not permit dark colored or discolored hydrogels. Thus, antimicrobial compositions, particularly hydrogels that carry greater amounts of active silver compound(s) and yet are not dark colored when made or darkened prematurely in the packaged form may be useful. Furthermore, antimicrobial compositions that possess pH near neutral and are robust against pH drift into the acidic range may also be useful. In addition, antimicrobial hydrogel compositions that are clear to aid in the monitoring of healing wounds and that are able to provide moisture management may provide further utility in practice.
To provide a robust and effective antimicrobial hydrogel composition starts with a robust and effective antimicrobial active agent. Among the actives, in theory silver is quite effective because at therapeutic use levels it is non-toxic and there is history of its safe use among clinicians for over hundred years. Besides, there is practically no risk of common pathogens developing resistance to silver due to its multi-prong disruption of the bacterial growth cycle. In contrast, the popular antibiotics are already becoming ineffective as resistant strains of microorganisms are slowly emerging, which is an unintended outcome of their overuse. Other antimicrobials such as biguanides and chlorohexidine compounds may be potentially useful but they have toxicity issues and so may not work well.
However, despite the promise of silver, products with silver have not been as widespread in use. That's because an overwhelming majority of silver compounds are prone to heat and light induced discoloration and hence are not robust. Often those that are sufficiently resistant are sparingly soluble in water, e.g., silver sulfadiazine. For example, since the introduction of silver sulfadiazine forty years ago, there have been no reports of any silver chemistry that have matched or exceeded its discoloration resistance. Because of poor solubility in practically all solvents, silver sulfadiazine has been met with limited success. Given that there have been reports of silver sulfadiazine as not being as effective against microorganisms that have developed resistance to sulfonamides, going forward it is less likely to be the active silver compound of choice for device manufacturers and formulators. Further, the solubility problem in general can lead to product quality issues, which may increase use levels to achieve efficacy and therefore make manufacturing tricky. While there is no match to silver's broad spectrum efficacy, silver containing products when in contact with body parts or skin can cause staining. Finally, the unpredictability of discoloration in silver containing devices may lead to poor yields in manufacturing, quality issues and a short shelf life. Various approaches to stabilization of silver in devices and compositions have been developed, but they have had limited utility due to their device specificity and limited implementation. Thus, an antimicrobial silver compound or a group of compounds that can provide more broadly robust resistance to heat and light induced discoloration and yet be relatively straightforward to incorporate into devices and compositions including hydrogels is lacking.
The inventor has recognized these issues and herein describes antimicrobial compositions that comprise silver cyanurate derivatives that hitherto were not investigated as antimicrobial actives. Antimicrobial devices comprising said compounds are also contemplated by the present disclosure. In one example, the antimicrobial compositions are hydrogels. The hydrogels are smooth, viscous, thixotropic, clear to translucent, readily spreadable under shear forces generated in topical use. Features of said antimicrobial compositions are clarity, ability to resist light and heat induced discoloration despite comprising active silver compounds at higher loadings. Some example hydrogel embodiments of the present disclosure are able to resist discoloration due to sunlight exposure or elevated temperatures of steam sterilization without compromising antimicrobial activity. The ability of said hydrogel compositions to withstand sunlight and elevated temperatures without discoloration while maintaining its antimicrobial effectiveness is a distinguishing feature of the present disclosure. Put another way, the robust thermal stability of said hydrogels precludes special storage conditions or shipping requirements and translates into practically an indefinite shelf life.
The antimicrobial hydrogel compositions of the present disclosure are non-staining to the skin and at use levels envisioned non-toxic to humans and animals. They possess effective broad spectrum antimicrobial activity against substantially all common pathogens: bacteria including MRSA and VRE, yeasts and fungi, but at higher silver loadings may be effective against, amoeba, protozoa, virus, etc. The said hydrogel compositions are suitable for use in the treatment of acute and chronic wounds that diabetics suffer, first and second degree burns and wounds on mucous membranes. When compounded appropriately they are effective and safe OTC products to treat minor cuts, burns and abrasions with minimal risk of staining. The hydrogels promote and accelerate wound healing by reducing bio-burden and promoting moisture management of low to moderate exuding wounds.
The present disclosure further provides methods of using a group of silver cyanurate compounds as antimicrobials. The compounds are inert to heat (steam sterilization temperatures) and light (direct sunlight), relatively easy to synthesize and incorporate into compositions and devices. To impart antimicrobial properties to compositions, they are derived simply by reacting metal cyanurates with soluble silver salts in solutions in situ or formed separately either individually or as a mixture and then compounded. Though sparingly soluble in water, when compounded into antimicrobial hydrogels at effective use levels, surprisingly they do not adversely affect gel transparency. Methods of making antimicrobial devices and compositions comprising said compounds for use as wound care products or patient care products are contemplated by the present disclosure. Examples of non-medical devices and their applications are provided.